Life expectancies for people living with HIV remain lower than for the general population, but thanks to the success of combination antiretroviral therapy (ART), HIV-infected individuals are living longer than ever before. It is estimated that half of the HIV/AIDS population in the US are now 50 years or older. This increased longevity is accompanied by increased prevalence and earlier incidence of non-AIDS age- related comorbidities including renal, hepatic, pulmonary, cardiovascular, neurocognitive, and skeletal disease. The mechanisms underlying these conditions remain poorly understood but inflammation driven by a damaged immune response likely contributes significantly to end organ damage. Ameliorating these comorbidities is increasingly becoming a major challenge in HIV disease management. HIV infection leads to severe impairment of the B cell compartment, which is not completely reversed by ART and manifests as B cell hyperactivity coupled paradoxically with hypo-responsiveness to natural non-HIV infections and vaccinations, due to impaired production of antigen-specific antibodies. While these aspects of B cell dysfunction have been the subject of intense research for the past two decades, emerging evidence now suggests that HIV-induced B cell dysfunction may have far-reaching consequences beyond impaired antibody responses to infections. Bisphosphonates are small-molecule inhibitors of bone resorption clinically approved for the treatment of osteoporotic conditions. Importantly, recent studies in bisphosphonate-treated mice unexpectedly showed increased generalized antigen (Ag)-specific humoral immune responses. Bisphosphonates are widely used in clinical settings and may thus be an attractive agent for mitigating B cell dysfunction, enhancing humoral immune responses, attenuating inflammation and ameliorating end-organ complications in HIV-infected people. We hypothesize that HIV-induced B cell dysfunction is integral to the development of a global pro-inflammatory state that contributes to end-organ impairment in chronic HIV-infection. Moderating and/or reversing this B cell dysfunction may mitigate or prevent organ damage in the aging HIV/AIDS population. To test this hypothesis, we will investigate whether this pro-inflammatory state can be ameliorated by treatment with a potent long acting bisphosphonates, zoledronic acid. (End of Abstract)